Project Summary: Cigarette smoke exposure and biomass combustion can lead to the development of Chronic Obstructive Pulmonary Disease (COPD) over time. However, not all individuals exposed to biomass or cigarette smoke will develop disease. The susceptibility to lung inflammation and emphysema in COPD has been extensively investigated from the aspect of the immune system response and proteinase activation. However, the interaction between cigarette smoke and the microbiome could provide insight into patient vulnerability. Studies in other organ systems have shown that the microbiome, which can dramatically differ from one individual to another, can influence the inflammatory response and disease development. With increasing studies revealing the existence of and the dynamic changes in the lung microbiota after injury, research of the microbiome opens new opportunities to deepen the understanding of lung pathogenesis during disease. We hypothesize that dynamic changes in microbiome profiles are associated with the progression of COPD whereas the initial state of microbiome profiles could play an important role in COPD susceptibility. We will therefore test this hypothesis by examining the profile of the lung and gut microbiota in several strains of mice of varying disease susceptibility exposed to cigarette smoke and identify correlations with lung inflammation and emphysema development. We also seek to define the dynamic changes in microbiome associated with COPD progression and compare the interaction between the gut and the lung microbiome. Our preliminary studies have identified decreased probiotic microbes in the gut of smoke exposed animals correlating with inflammation in the susceptible strains. We therefore plan to explore microbiome modulatory interventions, including supplementing probiotics and anti-inflammatory short-chain fatty acids, to identify whether disease susceptibility can be attenuated. These studies will allow the development of a mechanistic hypothesis and potential therapeutic interventions that alter the microbiome and protect the lung from developing injury. !